2015CAR-T峰会报道

Following the hugely successful CAR-T Summit in Boston, the team here at Hanson Wade and I would like to say a big thank to all those who participated in the event.

Putting together these meetings is never possible without the support of our partners and I’d like to take the time to thank them for their continued support as we grow the meeting and look to 2016.

The speakers whose research stimulated two days of conversation, interaction and solutions are integral to this meeting and I would like to thank each one of you for your huge contribution to the meeting. Your time and efforts were well received and we have been getting incredibly positive feedback.

A personal thank you to Dr. Zelig Eshhar, the father of CAR-Ts, for taking the time to chair the 2015 meeting and share with us all his years of expertise. Also a special thank you to Tom Whitehead for sharing his family’s personal journey, from learning about Emily’s cancer to her 3 and a half years cancer free. The story was both poignant and inspiring.

With many challenges on the horizon and still more questions than answers, the industry must come together and collaborate to succeed and with that we hope to see you all in 2016 to hear news on clinical updates, explore how to improve efficacy and potency of CAR-Ts, overcome the manufacturing and commercialization hurdles and bring these unique life changing therapies to market.

Introduction

The CAR-T summit held in Cambridge, Massachusetts on November 12-13, 2015 is the first of its kind, focusing solely on the application of Chimeric Antigen Receptors (CARs) in the therapeutic space. It assembled leaders from the pharmaceutical industry, academic institutions, service providers as well as non-profit organizations who have shared interests in bringing this promising therapy to the forefront of the battle against cancer. With an exceptional lineup of speakers and panelists over two days, we extensively discussed the status of the biology and economics behind CAR-Therapy, current issues plaguing this space as well as strategies for its future development. Below are some exclusive snippets from my two days. Omkar Kawalekar, Graduate Student at University of Pennsylvania.

Keynote Interviews

How can the CAR-T community avoid another “Biologics Bubble” & deliver on the early clinical promise?

What are the challenges and risks in the commercialization of the CAR-T business?

“Cost of goods sold aspect of disseminating this technology could be the bottle-neck”

This “tight squeeze” of four prominent leaders in the CAR-T space primarily discussed the translational prospects of the clinical success seen with this therapy so far. MR was of the opinion that the most important challenge was to continue to demonstrate the safety and clinical efficacy, while the risks involved controlling the cytokine syndrome, toxicity and how to mitigate and treat side-effects. BL mentioned that funding was a major risk until now, but the field should continue to remain on the “plateau of enlightenment” and not go downhill. However, he pointed out the regulatory approvals pose a looming challenge. Additionally, he believes that the processmoving ahead has to become more automated to accommodate the multifold increase in patient number as this therapy scales up, adding that the logistics of sourcing a product derived of patient cells and infusing these back into said patients was challenging too in terms of infrastructure, suppliers and labor. SW agreed with the issues on logistics. He gave an example of how Novartis acquired a manufacturing facility from Dendreon to centralize the ex vivo manipulation process of CAR-Ts. His goal is to disseminate the manufacturing knowhow and process to remote centers. BL believes that this technology is still a long way from being made available at community centers as the quality-control and delivery processes are complex. Both him and MR agreed that comparability between remote sites and major centers would be a big challenge. CH believes that the COGS (Cost Of Goods Sold) aspect of disseminating this technology could be the bottle-neck and thus he summarized that one cannot predict how long it would take for the transfer.

Durability and side-effects of CAR-Therapy

“A “living drug” that was persistent and durable”

From BL’s experience, Cytokine Release Syndrome (CRS) seemed to be the major side effect and its severity increased in patients with high disease burden. One strategy in such patients was to space out the infusion of CAR-T cells. In terms of durability of response, BL pointed out that analysis of patient cells and tumors was being conducted routinely using state-of-the-art assays including PCR, flow cytometry and micro-arrays these assays can be used to predict response to therapy on a patient by patient basis. As a reference, he talked about a 15-year old HIV CAR-T study performed with MR at CellGenesys. In this trial, CAR-Ts infused in HIV patients brought about a modest decrease in viral load by 0.3 logs, but the important take-home was that CAR-Ts could be detected in patients even up to 10 years post infusion. He called these cells a “living drug” that was persistent and durable. His current trials with leukemic patients have detectable CAR-T cells even 5 years post infusion. CH mentioned that durability can be enhanced by multiple injections and MR talked about certain intrinsic factors, such as CAR design and manufacturing process that could increase durability; and extrinsic factors, including tumor mass, types and duration of treatment the patient has undergone prior to the CAR-T therapy conditioning regimen. She suggested that these should be carefully studied to optimize durability of CAR-T therapy.

How to deal with adverse events

SW mentioned that there is a wealth of knowledge from the trials done so far that paves opportunities to learn and improve the therapy further by mitigating adverse events. BL on the other hand said that he has never seen any genotoxicity in the 100+ patients that his group has treated. MR shrewdly pointed out the adverse events associated with CAR-Therapies have been discussed out of context. She reminded everyone that the patients on CAR-Trials are highly refractory with only a survival rate of 4-8 months. CAR-T therapies have improved these survival rates,albeit to varying durations. Kite Pharma’s KTC19 trials have reported that patients’ B cells and immunoglobulin revert back to normal levels after reduction in tumor burden caused by CAR-T infusions.

Strategies to reduce cost of the technology

“One should pay close attention to the complexity drivers in the manufacturing process”

SW claimed that this was an obvious challenge. He stressed on how one should pay close attention to the complexity drivers in the manufacturing process. These include, but are not restricted to: regional regulatory environment, raw materials, logistical supply chain as well as the engineering approaches utilized.

Use of autologous versus allogeneic T cells as a starting material

“Any patient in any part of the world could receive this as an “off-the-shelf” therapy”

CH considers the autologous approach more effective, however, the future goal should focus on adopting the allogeneic model so that “any” patient in any part of the world could receive this as an “off-the-shelf” therapy. BL believes that allogeneic cells could be used for short-term purposes as a bridge to other therapies. He is currently working on an animal model at the University of Pennsylvania to investigate this idea further. MR seemed wary about this approach. She pointed out that graft versus host disease is a major issue, and genetic manipulation of allogeneic cells has not undergone long-term survival and safety testing to make it a reliable source of CAR-Ts for infusions.

B cell aplasia

Finally, as the session neared its close, a question raised by a member of the audience was regarding B cell aplasia and the cost associated with the intravenous replenishment of immunoglobulin (iv-Ig) post CD19 CAR-T therapy. BL mentioned that aplasia was related to the persistence of CAR-modified T cells grafted into the patient as well as the characteristics of the patient cells. Novel strategies, such as On/Off CARs and conditional CARs could help mitigate the need for iv-Ig issues. MR referred to the CAR constructs that her group at Kite Pharma has used which persist in patients for shorter time periods. Their studies suggest that patients with such CAR-T cells can come off iv-Ig sooner.

“It's rare to attend a conference and find every talk of interest. The inaugural CAR-T Summit 2015 assembled experts and front line companies to create an engaging, informative conference with just the right amount of networking opportunities.”——Jeff Till, Director, External Innovation, EMD Serono

The panel first discussed the use of preclinical models for studying CAR-T efficacy against solid tumors. BS suggested the use of syngeneic mouse models to try replicate efficacy of CAR-Ts seen in liquid tumors to solid tumors. Sheof course, warned that mouse models never reveal the most accurate representation of how such therapies would work in humans. HA attested to her views by reasoning out that the tumor biology and microenvironment in mice is very different from that in humans. SE was unconvinced about NSG mouse models that are currently being used by most investigators, due to the inherent limitations of the model. He pointed out that there have been only a handful of publications using syngeneic mouse models. MK was skeptical about the mechanisms of CAR-resistance developed in murine models and if they were truly representative of what happens in humans.

Immune response against CARs

A question rose about the risks involved in the induction of anti-CAR antibodies that could hamper CAR-effectiveness. To this, MK recalled that in a study done using a mesothelin-specific CAR at the University of Pennsylvania, the investigators saw some signs of antibodies against the CAR, but these did not have any adverse effects to the patients or to the effectiveness of the study. SE referred to the strategy his firm, Unum Therapeutics has developed. It uses antibody fragments, rather than single-chain variable fragments to reduce immunogenicity, they hope with enhanced success.

Use of peripheral blood versus tissue-resident T cells

Although all the panelists agreed that it was not yet possible to predict which of these would truly be “better”, SE talked about the differences in feasibility of acquiring the cells from these two different sources. He mentioned that the actual status of the patient at the time of apheresis or T cell acquisition would be an important factor to be considered.

Interactive Discussion: CAR-T in the Round

Bringing economically viable CAR-T therapies to market

“It is very difficult to put a price tag to the therapy”

This round table session focused around the economics behind the CAR-T therapy and the value it brings to the patients undergoing this treatment. First off, SB was reluctant to talk about the expected price of therapy and clarified that pricing would not be the focus of this discussion. He laid out the common platform of how investigational therapies are brought out to the market. These, as he pointed out are manufacture and supply, regulatory dossier, value dossier and outcomes-based reimbursements. To assess how the outcomes-based reimbursements would be gauged, one of the members pointed out that the NCCA rolled out parameters to measure and realize the value of the therapy. SB grouped the patient into three segments, based on the outcomes – (1) the “hope” segment where the value has not yet been realized, (2) The “loss” segment, which comprises of patients who have seen some positive indications with the therapy but not yet completely recovered, and (3) the “optimum” segment where the patient sees the highest value of the therapy.

However, it would be very difficult for the payer to allocate patients into these groups solely based on medical indications/outcomes. This in turn makes it very difficult to put a price tag to the therapy.

Other questions raised during the discussion and which could not be answered to any satisfactory consensus amongst the crowd, included:

1. How may doses per patient?

2. What would be the cost per dose or per regimen?

3. When would the payments be made – before or after the therapy/outcomes?

4.Does the hospital determine the cost?

5.What about the follow-up costs?

6. Is affordability going to be more important than cost-effectiveness?

“CAR-T technology is on the brink of becoming the new standard of care to treat cancer”

With all these questions yet to be addressed, SB concluded that the CAR-T community has truly generated a disruptive strategy in the fight against cancer. He made an analogy to Rolls Royce, the car company that makes aircraft engines and Nespresso, a luxury café whose major sales are now from home coffee-brewing machines. He left the crowd to ponder over how both these firms have come out to be the most widely acknowledged brands in their respective arenas, having disrupted competition’s business – and how the CAR-T technology is on the brink of becoming the new standard of care to treat cancer.

“The speakers were truly all great. The meeting was a great update on the state of CAR T cell field from all the major players.”——Neil Michaud, Associate Director R&D Qualitative Analytics, Takeda

Panel Discussion：How to Drive Down your Direct Cost of Goods and Foster Innovation to Execute a Commercially Viable CAR-T Therapy?

2020 From the Rear View Mirror

UA began the panel by setting that stage and painting a picture 5 years in the future. He transported us to 2020 and asked us to imagine adoptive cell immunotherapies had become a reality; they were accessible to patients around the world affordably. They were in the form of CARs and possibly other therapies treating hematological malignancies. There had also been significant progress in solid tumors.

He then asked the panel to reflect back from 2020 and think about how hindsight would change what they wish they had focused on in 2015?

PH highlighted that most of senior management tend to think in terms of margins. For example, what do we need to do to create a commercially viable margin protected product? He posed this interesting question base on the paradigm that cell and gene therapy is currently facing. There was a rapid transition from academia to industry however; they weren’t able to evaluate those processes that are used in a clinical setting vs. move to a process that is more specific to scaling up, he then went on to add the topic of value to the discussion.

The Value Proposition

AH talked about GSK factoring two important aspects into the value proposition conversation; one being modularity - different components of technology that have to come together in the right way to work together efficiently and effectively and the second being supply chain optimization. AH continues by highlighting the myriad challenges required to overcome both these things but finishes by stating at least directionally those two things, modularity and supply chain optimization will drive success.

Labor As A Cost of Manufacturing

TB brought in an additional paradigm to consider labor as a major part of the costs of manufacturing, particularly when thinking of working in a clean room to the tune of thousands of patients, it becomes quite a challenge that perhaps automation of all or some of the process will eventually help to overcome. As a final point he also mentioned quality control as an expensive process, each of the individual assays themselves are processes of their own and can also be quite labor intensive, particularly potency assays.

The panel went on to discuss the above challenges more extensively and highlighted the challenge of globalizing this type of therapy and integrating a supply chain into your development strategy.

UA closes by highlighting the varying efforts happening in the space throughout all the aspects of value chain, be that the starting material, thinking about cost of goods in the raw material setting, thinking about the time and place when it comes to indirect cost of goods as well.

Finally, he mentions that there is clearly a vision forming that CAR-T therapies could be scalable, adaptable, profitable systems, but this will necessitate courage and further investment over the next few years.

Conclusion

The final presentation at the CAR-T summit didn’t leave a dry eye in the room. We heard from Tom Whitehead, the father of Emily Whitehead (the first patient to receive CAR-T therapy) and co-founder of the Emily Whitehead Foundation. Tom gave a very poignant and heartfelt presentation, sharing his and his families journey from diagnosis to receiving CAR-T therapy, the side effects that followed and seeing Emily come through all this and in remission three and a half years later. This presentation rounded off nicely why everyone in this room was doing what they were doing, putting into perspective what success in this field could mean for thousands of patients. Thus concluding two days full of discussions on the variety of ways to streamline CAR-T discovery, design and development and optimize on the future manufacturing, commercialization and global distribution strategies. There is still a long way to go and this meeting highlighted the many possibilities moving forward despite this, let us not forget how far the industry has already come.